Is germ-line genome modification ethically justified?

As the normative objections to (human) germline genome editing cannot convincingly justify a categorical prohibition of such editing, its present prohibition should be replaced by a strict regulation, i.e. a conditional allowance. If safe and effective, germline genome editing may become a useful reproductive option.</p

Dynamics and Ethics of Comprehensive Preimplantation Genetic Testing. A Review of the Challenges

BACKGROUND: Genetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and is to be expected that also whole genome sequencing of blastomeres will become possible. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, but also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues. METHODS: The paper is a joint endeavour by the presenters at an explorative 'campus meeting' organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands). RESULTS: The increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. “Smart combinations” of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others. CONCLUSION: As comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.This article was written by Dr Ainsley Newson during the time of her employment with the University of Bristol, UK (2006-2012). Self-archived in the Sydney eScholarship Repository with permission of Bristol University, Sept 2014

Recommendations for sepsis management in resource-limited settings

PURPOSE: To provide clinicians practicing in resource-limited settings with a framework to improve the diagnosis and treatment of pediatric and adult patients with sepsis. METHODS: The medical literature on sepsis management was reviewed. Specific attention was paid to identify clinical evidence on sepsis management from resource-limited settings. RESULTS: Recommendations are grouped into acute and post-acute interventions. Acute interventions include liberal fluid resuscitation to achieve adequate tissue perfusion, normal heart rate and arterial blood pressure, use of epinephrine or dopamine for inadequate tissue perfusion despite fluid resuscitation, frequent measurement of arterial blood pressure in hemodynamically unstable patients, administration of hydrocortisone or prednisolone to patients requiring catecholamines, oxygen administration to achieve an oxygen saturation &gt;90%, semi-recumbent and/or lateral position, non-invasive ventilation for increased work of breathing or hypoxemia despite oxygen therapy, timely administration of adequate antimicrobials, thorough clinical investigation for infectious source identification, fluid/tissue sampling and microbiological work-up, removal, drainage or debridement of the infectious source. Post-acute interventions include regular re-assessment of antimicrobial therapy, administration of antimicrobials for an adequate but not prolonged duration, avoidance of hypoglycemia, pharmacological or mechanical deep vein thrombosis prophylaxis, resumption of oral food intake after resuscitation and regaining of consciousness, careful use of opioids and sedatives, early mobilization, and active weaning of invasive support. Specific considerations for malaria, puerperal sepsis and HIV/AIDS patients with sepsis are included. CONCLUSION: Only scarce evidence exists for the management of pediatric and adult sepsis in resource-limited settings. The presented recommendations may help to improve sepsis management in middle- and low-income countries

Preimplantation genetic testing for more than one genetic condition:clinical and ethical considerations and dilemmas

STUDY QUESTION: Which clinical and ethical aspects of preimplantation genetic testing for monogenic disorders or structural rearrangements (PGT-M, PGT-SR) should be considered when accepting requests and counselling couples for PGT when applied for more than one condition (combination-PGT; cPGT-M/SR)? SUMMARY ANSWER: cPGT is a feasible extension of the practice of PGT-M/SR that may require adapting the criteria many countries have in place with regard to indications-setting for PGT-M/SR, while leading to complex choices that require timely counselling and information. WHAT IS KNOWN ALREADY: Although PGT-M/SR is usually performed to prevent transmission of one disorder, requests for PGTM/SR for more than one condition (cPGT-M/SR) are becoming less exceptional. However, knowledge about implications for a responsible application of such treatments is lacking. STUDY DESIGN, SIZE, DURATION: Retrospective review of all (40) PGT-M/SR applications concerning more than one genetic condition over the period 1995-2018 in the files of the Dutch national PGT centre. This comprises all relevant national data since the start of PGT in the Netherlands. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Data regarding cPGT-M/SR cases were collected by means of reviewing medical files of couples applying for cPGT-M/SR. Ethical challenges arising with cPGT-M/SR were explored against the background of PGT-M/SR regulations in several European countries, as well as of relevant ESHRE-guidance regarding both indications-setting and transfer-decisions. MAIN RESULTS AND THE ROLE OF CHANCE: We report 40 couples applying for cPGT-M/SR of which 16 couples started their IVF treatment. Together they underwent 39 IVF cycles leading to the birth of five healthy children. Of the couples applying for cPGT, 45% differentiated between a primary and secondary condition in terms of perceived severity. In the light of an altered balance of benefits and drawbacks, we argue the 'high risk of a serious condition' standard that many countries uphold as governing indications-setting, should be lowered for secondary conditions in couples who already have an indication for PGT-M/SR. As a consequence of cPGT, professionals will more often be confronted with requests for transferring embryos known to be affected with a condition that they were tested for. In line with ESHRE guidance, such transfers may well be acceptable, on the condition of avoiding a high risk of a child with a seriously diminished quality of life. LIMITATIONS, REASONS FOR CAUTION: We are the first to give an overview of cPGT-M/SR treatments. Retrospective analysis was performed using national data, possibly not reflecting current trends worldwide. WIDER IMPLICATIONS OF THE FINDINGS: Our observations have led to recommendations for cPGT-M/SR that may add to centre policy making and to the formulation of professional guidelines. Given that the introduction of generic methods for genomic analysis in PGT will regularly yield incidental findings leading to transfer requests with these same challenges, the importance of our discussion exceeds the present discussion of cPGT

Hyponatremia in Severe Malaria: Evidence for an Appropriate Anti-diuretic Hormone Response to Hypovolemia

Although hyponatremia occurs in most patients with severe malaria, its pathogenesis, prognostic significance, and optimal management have not been established. Clinical and biochemical data were prospectively collected from 171 consecutive Bangladeshi adults with severe malaria. On admission, 57% of patients were hyponatremic. Plasma sodium and Glasgow Coma Score were inversely related (rs = −0.36, P < 0.0001). Plasma antidiuretic hormone concentrations were similar in hyponatremic and normonatremic patients (median, range: 6.1, 2.3–85.3 versus 32.7, 3.0–56.4 pmol/L; P = 0.19). Mortality was lower in hyponatremic than normonatremic patients (31.6% versus 51.4%; odds ratio [95% confidence interval]: 0.44 [0.23–0.82]; P = 0.01 by univariate analysis). Plasma sodium normalized with crystalloid rehydration from (median, range) 127 (123–140) mmol/L on admission to 136 (128–149) mmol/L at 24 hours (P = 0.01). Hyponatremia in adults with severe malaria is common and associated with preserved consciousness and decreased mortality. It likely reflects continued oral hypotonic fluid intake in the setting of hypovolemia and requires no therapy beyond rehydration

Cost-Effectiveness of Pre-Referral Antimalarial, Antibacterial, and Combined Rectal Formulations for Severe Febrile Illness

BACKGROUND: Malaria and bacterial infections account for most infectious disease deaths in developing countries. Prompt treatment saves lives, but rapid deterioration often prevents the use of oral therapies; delays in reaching health facilities providing parenteral interventions are common. Rapidly and reliably absorbed antimalarial/antibacterial rectal formulations used in the community could prevent deaths and disabilities. Rectal antimalarial treatments are currently available; rectal antibacterial treatments are yet to be developed. Assessment of the likely cost-effectiveness of these interventions will inform research priorities and implementation. METHODS AND FINDINGS: The burden of malaria and bacterial infections worldwide and in Sub-Saharan and Southern Africa (SSA) and South and South-East Asia (SEA) was summarised using published data. The additional healthcare costs (USD) per death and per Disability Adjusted Life Year (DALY) avoided following pre-referral treatment of severe febrile illness with rectal antimalarials, antibacterials or combined antimalarial/antibacterials in populations at malaria risk in SSA/SEA were assessed. 46 million severe malaria and bacterial infections and 5 million deaths occur worldwide each year, mostly in SSA/SEA. At annual delivery costs of 0.02 dollars/capita and 100% coverage, rectal antimalarials (2 dollars per dose) would avert 240,000 deaths in SSA and 7,000 deaths in SEA at 5 and 177 dollars per DALY avoided, respectively; rectal antibacterials (2 dollars per dose) would avert 130,000 deaths in SSA and 27,000 deaths in SEA at 19 and 97 dollars per DALY avoided, respectively. Combined rectal formulations (2.50 dollars per dose) would avert 370,000 deaths in SSA and 33,000 deaths in SEA at 8 and 79 dollars per DALY avoided, respectively, and are a cost-effective alternative to rectal antimalarials or antibacterials alone. CONCLUSIONS: Antimalarial, antibacterial and combined rectal formulations are likely to be cost-effective interventions for severe febrile illness in the community. Attention should focus on developing effective rectal antibacterials and ensuring that these lifesaving treatments are used in a cost-effective manner

The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis

BackgroundThrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined.MethodsClinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient&rsquo;s platelet count on admission to hospital and their subsequent clinical course.ResultsOn admission, 614 patients (94.9%) were thrombocytopenic (platelet count &lt;150&thinsp;&times;&thinsp;109/L) and 328 (50.7%) had a platelet count &lt;50&thinsp;&times;&thinsp;109/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs&thinsp;=&thinsp;&minus;0.28, P&thinsp;=&thinsp;0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs&thinsp;=&thinsp;&minus;0.31, P&thinsp;=&thinsp;0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs&thinsp;=&thinsp;&minus;0.21, P &lt;0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52)&thinsp;&times;&thinsp;109/L versus 50 (34 to 78)&thinsp;&times;&thinsp;109/L in survivors; P &lt;0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count &lt;20&thinsp;&times;&thinsp;109/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study.ConclusionsThrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management