Laboratory selection for resistance to starvation has been conducted under relatively controlled conditions to investigate direct and correlated responses to artificial selection. With regards to starvation resistance, there are three physiological routes by which the trait can evolve: resource accumulation, energy conservation and starvation tolerance. A majority of energetic compounds and macromolecules including triglycerides, trehalose and other sugars, and soluble protein increased in abundance as a result of selection. Movement was additionally investigated with selected males moving less than control males and selected females exhibiting a similar response to selection. Results obtained from this study supported two of the possible evolutionary mechanisms for adaptation to starvation: energy compound storage and conservation. If the response to selection is based on an evolutionarily conserved pattern of genetic correlations (elevated lipid, elevated sugars and reduced movement), then the response to selection is medically relevant and the genetic architecture should be investigated in depth.

ImportanceThe effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.ObjectiveTo evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19.Design, Setting, and ParticipantsACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US.InterventionsParticipants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774).Main Outcomes and MeasuresTime to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28.ResultsAmong 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]).Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

ImportanceThe effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear.ObjectiveTo evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US.Design, Setting, and ParticipantsThe ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US.InterventionsParticipants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo.Main Outcomes and MeasuresThe primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28.ResultsAmong 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups.Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

The ultimate treatment goal of diabetes is to preserve and restore islet cell function. Treatment of certain diabetic animal models with incretins has been reported to preserve and possibly enhance islet function and promote islet cell growth. The studies reported here detail islet cell anatomy in animals chronically treated with the incretin analog, liraglutide. Our aim was to quantitatively and qualitatively analyze islet cells from diabetic animals treated with vehicle (control) or liraglutide to determine whether normal islet cell anatomy is maintained or enhanced with pharmaceutical treatment. We harvested pancreata from liraglutide and vehicle-treated Zucker Diabetic Fatty (ZDF) rats to examine islet structure and function and obtain isolated islets. Twelve-week-old male rats were assigned to 3 groups: (1) liraglutide-treated diabetic, (2) vehicle-treated diabetic, and (3) lean non-diabetic. Liraglutide was given SC twice daily for 9 weeks. As expected, liraglutide treatment reduced body weight by 15% compared to the vehicle-treated animals, eventually to levels that were not different from lean controls. At the termination of the study, blood glucose was significantly less in the liraglutide-treated rats compared to vehicle treated controls (485.8±22.5 and 547.2±33.1mg/dl, respectively). Insulin content/islet (measured by immunohistochemistry) was 34.2±0.7 pixel units in vehicle-treated rats, and 54.9±0.6 in the liraglutide-treated animals. Glucose-stimulated insulin secretion from isolated islets (measured as the stimulation index) was maintained in the liraglutide-treated rats, but not in the vehicle-treated. However, liraglutide did not preserve normal islet architecture. There was a decrease in the glucagon-positive area/islet and in the α-cell numbers/area with liraglutide treatment (6.5 cells/field), compared to vehicle (17.9 cells/field). There was an increase in β-cell numbers, the β- to α-cell ratio that was statistically higher in the liraglutide-treated rats (24.3±4.4) compared to vehicle (9.1±2.8). Disrupted mitochondria were more commonly observed in the α-cells (51.9±10.3% of cells) than in the β-cells (27.2±4.4%) in the liraglutide-treated group. While liraglutide enhanced or maintained growth and function of certain islet cells, the overall ratio of α- to β-cells was decreased and there was an absolute reduction in islet α-cell content. There was selective disruption of intracellular α-cell organelles, representing an uncoupling of the bihormonal islet signaling that is required for normal metabolic regulation. The relevance of the findings to long-term liraglutide treatment in people with diabetes is unknown and should be investigated in appropriately designed clinical studies.

This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder. This chapter will provide an overview of each medication's indication for use, history of development, pharmacology, metabolism, dosing recommendations, onset of action, use in special populations, safety and tolerability, adverse effects, potential interactions with additional medications, and data regarding possible overdose with available treatments.Bupropion was initially developed for its combined effects on the norepinephrine and dopamine neurotransmitters. Currently, bupropion is the only antidepressant on the market in the United States with no appreciable activity on serotonin concentrations in the central nervous system. Bupropion is extensively metabolized in humans into three active metabolites including hydroxybupropion, threohydrobupropion, and erythrohydrobuproprion each with substantial antidepressant activity. The most serious side effect of bupropion is the development of seizures, so the dose must be gradually titrated to a maximum dose of 450 mg per day of the immediate-release formulation and 400 mg per day of the sustained-release formulation. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. The onset of action of bupropion is 2 weeks with full efficacy attained at 4 weeks of treatment. Bupropion produced similar depression remission rates when compared to SSRIs with a median time to relapse of 44 weeks. Bupropion has additionally been approved for smoking cessation and may have a combined role in treating nicotine cravings and depression.Mirtazapine has a unique method of action by enhancing norepinephrine and serotonin neurotransmission by blocking the alpha-2 presynaptic adrenoceptors resulting in increased release of serotonin at the nerve terminals. Mirtazapine additionally binds to the 5-HT, 5-HT, and H receptors resulting in increased sedation, which is the most common side effect. Additional side effects include increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Mirtazapine is unlike any other antidepressant in that it also has a hormonal effect that reduces cortisol levels within the body. Patients on mirtazapine showed significant improvement in symptoms of major depressive disorder within the first 1-2 weeks of treatment with long-term studies at 40 weeks showing continued improvements in response rates in addition to lower relapse rates. ...

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ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts.ObservationsTo support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing clinical and laboratory infrastructure, community partnerships, and research expertise to quickly pivot clinical trial sites to conduct COVID-19 vaccine trials as soon as the investigational products were ready for phase 3 testing. The mission of CoVPN was to operationalize phase 3 vaccine trials using harmonized protocols, laboratory assays, and a single data and safety monitoring board to oversee the various studies. These trials, while staggered in time of initiation, overlapped in time and course of conduct and ultimately led to the successful completion of multiple studies and US Food and Drug Administration–licensed or –authorized vaccines, the first of which was available to the public less than 1 year from the discovery of the virus.Conclusions and RelevanceThis Special Communication describes the design, geographic distribution, and underlying principles of conduct of these efficacy trials and summarizes data from 136 382 prospectively followed-up participants, including more than 2500 with documented COVID-19. These successful efforts can be replicated for other important research initiatives and point to the importance of investments in clinical trial infrastructure integral to pandemic preparedness.

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