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T and B lymphocytes, which are part of a group of immune cells commonly called white blood cells, work together to eliminate foreign invaders in the body such as viruses. However, certain diseases can arise when T and B cells are activated at inappropriate times, including autoimmune disorders and various cancers. In a recent article published in Nature Communications, a team led by researchers at Tokyo Medical and Dental University (TMDU) describe a technology called a heteroduplex oligonucleotide (HDO) that they developed to deliver to lymphocytes and regulate their functions.
Gene expression is at the root of controlling cellular activity. Disease can result when certain genes are either improperly turned off or are uncontrollably expressed. Therefore, scientists have aimed to develop therapeutic methods to restore gene expression levels to their healthy state, ideally only in the abnormal cells. One such modality is delivering specifically engineered DNA or RNA molecules that can locate the misexpressed gene messages and direct the cell to lower them back to normal levels. However, the most difficult part of this is ensuring the therapeutic molecules can efficiently reach their proper destination without being degraded by the cell.
“Our team designed a DNA/RNA hybrid molecule called an HDO,” says lead author of the study Masaki Ohyagi. “The specific sequence of the HDO can be altered to target a particular gene of interest, while its backbone makes it stable within cells.”
A key part of the team’s HDO design is the addition of a molecule called α-tocopherol, which is crucial to its proper delivery. Because α-tocopherol is essential for proper lymphocytic immune responses, adding this allows the HDO to be delivered within peripheral blood and directed to lymphocytes. The team designed HDOs for several mouse genes and then intravenously injected them into lab mice.
“We found that our HDO technology was able to specifically silence these genes in mouse lymphocytes more robustly and stably, and also with less toxicity, than other previous versions of this method,” states Takanori Yokota, senior author of the article. “Our studies also showed that the HDOs enter these cells through a process called endocytosis.”
After finding that their technology was effective at gene silencing, the TMDU team investigated if it could be useful as a disease treatment. They designed an HDO targeting a gene called Itga4, which is central to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS).
“Intravenously injecting these mice with an Itga4-targeting HDO delayed the onset and improved EAE symptoms and reduced both inflammatory cell infiltration and spinal cord demyelination,” explains Ohyagi.
This work demonstrates the powerful gene silencing effects of the HDO technology, as well as its superior delivery capabilities relative to other similar methods. Most significantly, the Itga4-specific HDO was able to improve outcomes in an MS mouse model, suggesting it may be useful as a novel therapeutic that could be developed for human immune-mediated diseases.
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Materials provided by Tokyo Medical and Dental University. Note: Content may be edited for style and length.

The largest study to date has confirmed the link between the gut microbiome and the response to cancer immunotherapy therapy for melanoma.
The study is published today in Nature Medicine and co-ordinated by King’s College London, CIBIO Department of the University of Trento and European Institute of Oncology in Italy, University of Groningen in the Netherlands and funded by the Seerave Foundation.
Dr Karla Lee, clinical researcher at King’s College London and first author of the study, said: “Preliminary studies on a limited number of patients have suggested that the gut microbiome, as an immune system regulator, plays a role in the response of each patient to cancer immunotherapy, and particularly in the case of melanoma. This new study could have a major impact on oncology and medicine in general.”
The microbiome, the set of microorganisms that live in the intestines, can be altered through dietary changes, next generation probiotics and faecal transplantation. This change is in turn modifying the microbiome’s action on the immune system. Understanding the characteristics of the microbiome can enable treating clinicians to alter a patient’s microbiome accordingly before starting treatment. Less than 50% of patients respond positively to immunotherapy for melanoma so finding strategies to increase the number of positive responders is crucial.
The study put together the largest cohort of patients with melanoma and samples of their gut microbiome from five clinical centres in the UK, the Netherland and Spain. Researchers carried out a large-scale metagenomic study — sequencing of the gut microbiome — to investigate whether there is an association between the composition and function of the gut microbiome and response to immunotherapy.
Results confirmed a complex association as it involves different bacterial species in different patient cohorts. The presence of three types of bacteria (Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila) seem to be associated with a better immune response. An additional finding was that the microbiome itself is strongly influenced by factors including patient constitution, use of proton pump inhibitors and diet that should be considered in future longitudinal studies.
Co-author Professor Tim Spector from King’s College London said: “This study shows the chances of survival based on healthy microbes nearly doubled between subgroups. The ultimate goal is to identify which specific features of the microbiome are directly influencing the clinical benefits of immunotherapy to exploit these features in new personalised approaches to support cancer immunotherapy. But in the meantime, this study highlights the potential impact of good diet and gut health on chances of survival in patients undergoing immunotherapy.”
Co-author Professor Nicola Segata from University of Trento said: “Our study shows that studying the microbiome is important to improve and personalise immunotherapy treatments for melanoma. However, it also suggests that because of the person-to-person variability of the gut microbiome, even larger studies must be carried out to understand the specific gut microbial features that are more likely to lead to a positive response to immunotherapy.”
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Materials provided by King’s College London. Note: Content may be edited for style and length.

Many people have to take statins to lower their cholesterol levels. But statins may be able to do even more: Researchers report that these drugs inhibit a gene that promotes cancer cell metastasis.
Cancer patients rarely die from the primary tumor but rather from the metastases — even after successful tumor surgery. This is because cancer cells sometimes spread to other parts of body early in the disease, when the tumor is still very small and may not have even been discovered yet. To do this they must break away from the extracellular matrix and migrate into neighboring lymphatic vessels or blood vessels that transport them to new tissue, where they settle and proliferate.
Understanding the molecular mechanisms of metastasis is therefore a key piece of the puzzle in the fight against cancer. More than ten years ago, Professor Ulrike Stein and her lab at the Experimental and Clinical Research Center (ECRC) were able to discover an important driver of this process in human colorectal cancer: the metastasis-associated in colon cancer 1 (MACC1) gene. The ECRC is a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité — Universitätsmedizin Berlin.
Drug screening identified statins
When cancer cells express MACC1, their ability to proliferate, move around the body, and invade other tissues is enhanced. “Many types of cancers spread only in patients with high MACC1 expression,” Stein explains. MACC1’s role as a key factor and biomarker of tumor growth and metastasis — not only in colorectal cancer, but in more than 20 solid tumors such as gastric, liver and breast cancer — has since been studied by many other researchers worldwide and confirmed in more than 300 publications. Now together with Dr. Robert Preißner of Charité, Stein has discovered what could disrupt metastatic progression in such cases: Statins, which are prescribed as cholesterol-lowering drugs, inhibit MACC1 expression in tumor cells. The scientists are presenting their findings in the journal Clinical and Translational Medicine.
In their search for MACC1 inhibitors, the researchers conducted high-throughput drug screening with colleagues at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. They independently hit upon statins. They tested this discovery on various tumor cell lines, with favorable results: All seven drugs tested reduced MACC1 expression in the cells but to varying degrees. The scientists then administered the cholesterol inhibitors to genetically modified mice with increased MACC1 expression. This almost completely suppressed the formation of tumors and metastases in the animals. “What is particularly remarkable is that the benefits continued in the animals even after we reduced the dose relative to the amount that humans normally ingest,” Stein says.
Statins have one big advantage: they are already approved
Robert Preißner and scientists at the University of Virginia also examined data from a total of 300,000 patients who had been prescribed statins. This analysis found a correlation: “Patients taking statins had only half the incidence of cancer compared to the general population,” Preißner explains.
Stein advises against taking statins as a preventive measure without consulting a doctor and having their lipid levels checked, so as to ensure no serious side effects occur. “We are still at the very beginning,” the scientist stresses. “Cell lines and mice are not human beings, so we cannot directly transfer the results.” The experimental studies and retrospective data analysis will now be followed up by a clinical trial, she says. Only after that will it be possible to say with certainty whether statins actually prevent or reduce metastasis in patients with high MACC1 expression.
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Materials provided by Max Delbrück Center for Molecular Medicine in the Helmholtz Association. Original written by Jana Ehrhardt-Joswig. Note: Content may be edited for style and length.

Syringe services programs — sites where people who use drugs can access sterile syringes and dispose of injection equipment — often face political backlash. But a new study shows the effectiveness of these programs in both curbing HIV transmission among people who use drugs and preventing future outbreaks.
In a rural American setting that had previously experienced one of the largest HIV outbreaks among people who use drugs, a simulation suggested that closing the existing syringe services programs would likely lead to a rebound HIV outbreak, with an almost 60% increase in infections among people who use drugs in five years.
Even closing the program temporarily would lead to an increase in cases of HIV, the study showed.
“Our work shows that shutting down syringe services programs has immediate and detrimental impacts on people who use drugs and the broader community,” said senior author Brandon Marshall, an associate professor of epidemiology at Brown University. “We should be expanding access and increasing sustainable funding to these programs to prevent future outbreaks.”
The analysis, published in the journal AIDS, presents the first study to the researchers’ knowledge to quantitatively examine the impact of syringe services program closure on HIV incidence.
Syringe services programs are community-based prevention programs that provide services such as referrals to substance use disorder treatment, access to and disposal of sterile syringes and injection equipment, and vaccination, testing and connections to care for infectious diseases. They’re effective in curbing the transmission of HIV — as long as they remain in operation, the researchers said.

Extract from the bark of the Neem tree may help treat and reduce the spread of coronavirus, according to a new study led by scientists at the University of Colorado Anschutz Medical Campus and the Indian Institute of Science Education and Research Kolkata.
The study, reported recently in the journal Virology, shows that components of Neem bark may target a wide range of viral proteins, suggesting its potential as an antiviral agent against emerging variants of coronaviruses (including SARS-CoV-2).
The Neem tree, indigenous to India, has been used for thousands of years for its anti-parasitic, anti-bacterial and antiviral properties. The bark extract has helped treat malaria, stomach and intestinal ulcers, skin diseases and many other diseases.
“The goal of this research is to develop a Neem-based medication that can reduce the risk of serious illness when someone is infected with coronaviruses,” said study co-author Maria Nagel, MD, research professor in the department of neurology and ophthalmology at the University of Colorado School of Medicine on the CU Anschutz Medical Campus.
“We hope that scientists won’t have to continuously develop new therapies every time a new SARS-CoV-2 variant emerges,” she said. “Just like how we take penicillin for strep throat, we envision taking the Neem-based drug for COVID, allowing us to resume our normal lives without fear of hospitalization and death.”
The scientists investigated the impact of the bark extract against coronaviruses in their laboratories. In India, researchers tested it in animal models and showed that it had antiviral properties against coronavirus. Using computer modeling, the researchers predicted that Neem bark extract will bind to the SARS-CoV-2 spike protein at various locations, preventing virus entry to host cells.
At CU Anschutz, Nagel’s lab tested the Neem bark extract in SARS-CoV-2 human lung cells. It proved as effective as a preventive drug for infection and also decreased virus replication and spread after infection.
“The next step in our research is to identify the specific components in Neem bark extract that are antiviral. Because these components bind to various regions of SARS-CoV-2, we believe that it will be effective on emerging variants with spike mutations,” said Nagel. “We will then determine the formulation of dosage for an antiviral drug to treat coronavirus infections.”
The scientists said this research could guide new antiviral therapeutic efforts to combat the ongoing pandemic, while holding out the promise for treating new coronavirus strains.
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Materials provided by University of Colorado Anschutz Medical Campus. Original written by Julia Milzer. Note: Content may be edited for style and length.

Schistosomiasis is a debilitating disease caused by a parasitic worm that develops in freshwater snails before infecting people. Knocking back snail populations with pesticides is one method to control the spread of the disease, also known as “snail fever.”
A new study led by Emory University, however, shows that schistosome transmission can actually be highest when freshwater snail populations are low. The Proceedings of the National Academy of Sciences published the study, the first to demonstrate how the size of a freshwater snail population relates to its parasitic infection rate.
“We’ve shown that the more snails you have in a freshwater source, the less dangerous each individual snail is, in terms of the number of parasites they’re releasing,” says David Civitello, an Emory assistant professor of biology and lead author of the study. “The incredible strength of our finding is that we’ve demonstrated the effect both in the field, using natural transmission sites, and in an experimental context, through outdoor laboratory experiments.”
The research carries important implications for policies aimed at reducing the transmission of schistosomiasis. Considered one of the most significant of the neglected tropical diseases, the parasites that cause schistosomiasis currently infect more than 200 million people.
“Our results suggest that if you apply a heavy dose of pesticides to reduce a snail population, the infectivity of the remaining snails might actually skyrocket,” Civitello says. “It’s basically impossible to kill every snail and so you set the stage for a rebound in infection risk. As the snail population begins to recover, our data tells us that this is a time with extremely high potential for transmission of the parasites to humans.”
Previous laboratory experiments had found that when an individual freshwater snail infected with the parasite is well fed, it can generate as many as thousands more parasites per day compared to an underfed snail. In fact, an underfed infected snail may generate as few as a single parasite per day.

Cutaneous T-cell lymphoma (CTCL) is an incurable, rare cancer of skin-homing T cells that is highly disfiguring and lethal at advanced stages. The most common form of CTCL, mycosis fungoides, is characterized by a cutaneous patch, plaque and/or tumor lesions. Another form, Sezary syndrome, is the leukemic variant of CTCL with circulating malignant T cells in the blood. Large cell transformation occurs in a subset of mycosis fungoides and Sezary patients heralding immediate transition to an aggressive large cell lymphoma. However, given the rare nature of CTCL, gathering adequate tissue specimens to investigate the tumor microenvironment at large cell transformation has been a significant roadblock to potential therapeutic advances.
In a new article published in Cancer Discovery, a journal of the American Association for Cancer Research, Moffitt Cancer Center researchers shared a comprehensive multiomics study from a rare cohort of 56 patients with transformed CTCL and identified several genomic alterations and oncogenic programs that may be potential novel therapeutic targets.
“While cancer death rates have significantly declined for many common cancers in the past decade, there is a sobering underrepresentation of this success in rare cancers, such as CTCL, particularly in the vulnerable racial minority groups,” said study senior author Pei-Ling Chen, M.D., Ph.D., associate member of the Pathology and Cutaneous Oncology Departments and member of the Moffitt Cutaneous Lymphoma Multidisciplinary Clinic, one of the largest CTCL referral centers in the U.S.
Moffitt researchers, in collaboration with scientists at MD Anderson Cancer Center, performed multiomics profiling of 70 biopsies and 16 fresh tissue specimens from patients with transformed CTCL and investigated the tumor ecosystem using integrative approaches spanning whole exome sequencing, single-cell RNAseq and immune profiling by single-cell V(D)J sequencing and multiplex immunofluorescence studies. The researchers discovered that the genomic landscape of transformed CTCL is characterized by a high tumor mutation burden and UV mutation signatures that are prognostic for survival. Importantly, transformed CTCL samples from Black/African American patients showed significantly lower contribution of UV signatures and enrichment of mutation signatures that are associated with defective DNA mismatch repair. The research team also identified several recurrently mutated pathways and exome-based driver events in transformed CTCL and showed dissimilarity in the genomic landscape of transformed T cells in skin versus leukemic T cells in blood, revealing opportunities to exploit differential or synergistic therapeutic vulnerabilities in the two body compartments at advanced stage disease.
To interrogate the transformed CTCL tumor ecosystem at single-cell resolution, the researchers then profiled 34,912 cells from 16 fresh tissue biopsies by single-cell RNA and V(D)J sequencing. The research team identified the core oncogenic programs that malignant T cells exploit at large cell transformation, including metabolic reprogramming toward oxidative phosphorylation, cellular plasticity, upregulation of MYC, E2F and macrophage migration inhibitory factor activities, and downregulation of MHC-I suggestive of immune surveillance escape. These signatures were further validated by pharmacologic perturbation studies using novel small molecule inhibitors of oxidative phosphorylation and MUC and multiplex immunofluorescence imaging.
“While further validation in larger cohorts and pre-clinical models are needed, our investigation provides a key resource to the community with the largest collection of transformed CTCL samples studied to date, the first comprehensive compendium of genomic alterations at large cell transformation, a blueprint for dissecting the T-cell lymphoma tumor microenvironment at single-cell resolution and identifies potential prognostic signatures and novel therapeutic targets in transformed CTCL. We anticipate results from this study can be extrapolated to other T-cell lymphomas and will help usher novel immunotherapeutic strategies to combat this currently incurable cancer,” said Chen.
While racial disparity is well-known to exist in CTCL, with Black and African American patients showing worse clinical outcomes, potential biological factors underlying this disparity are poorly understood. The researchers hope that their findings can provide insights into potential genomic correlate of this disparity. Future studies involving larger sample size from the vulnerable population and research into their tumor microenvironment for predictive biomarkers and novel therapeutic targets will hopefully help reduce racial disparity in CTCL.
This study was supported by the Moffitt Foundation, Moffitt Clinical Science Fund, Miles for Moffitt, Total Cancer Care, the Donald A. Adam Melanoma & Skin Cancer Center of Excellence and the National Cancer Institute (P30-CA076292, R01CA240434).

A new data analysis tool developed by Yale researchers has revealed the specific immune cell types associated with increased risk of death from COVID-19, they report Feb. 28 in the journal Nature Biotechnology.
Immune system cells such as T cells and antibody-producing B cells are known to provide broad protection against pathogens such as SARS-CoV-2, the virus that causes COVID-19. And large-scale data analyses of millions of cells have given scientists a broad overview of the immune system response to this particular virus. However, they have also found that some immune cell responses — including by cell types that are usually protective — can occasionally trigger deadly inflammation and death in patients.
Other data analysis tools that allow for examination down to the level of single cells have given scientists some clues about culprits in severe COVID cases. But such focused views often lack the context of particular cell groupings that might cause better or poorer outcomes.
The Multiscale PHATE tool, a machine learning tool developed at Yale, allows researchers to pass through all resolutions of data, from millions of cells to a single cell, within minutes. The technology builds on an algorithm called PHATE, created in the lab of Smita Krishnaswamy, associate professor of genetics and computer science, which overcomes many of the shortcomings of existing data visualization tools.
“Machine learning algorithms typically focus on a single resolution view of the data, ignoring information that can be found in other more focused views,” said Manik Kuchroo, a doctoral candidate at Yale School of Medicine who helped develop the technology and is co-lead author of the paper. “For this reason, we created Multiscale PHATE which allows users to zoom in and focus on specific subsets of their data to perform more detailed analysis.”
Kuchroo, who works in Krishnaswamy’s lab, used the new tool to analyze 55 million blood cells taken from 163 patients admitted to Yale New Haven Hospital with severe cases of COVID-19. Looking broadly, they found that high levels T cells seem to be protective against poor outcomes while high levels of two white blood cell types known as granulocytes and monocytes were associated with higher levels of mortality.
However, when the researchers drilled down to a more granular level they discovered that TH17, a helper T cell, was also associated with higher mortality when clustered with the immune system cells IL-17 and IFNG.
By measuring quantities of these cells in the blood, they could predict whether the patient lived or died with 83% accuracy, the researchers report.
“We were able to rank order risk factors of mortality to show which are the most dangerous,” Krishnaswamy said.
In theory, the new data analytical tool could be used to fine tune risk assessment in a host of diseases, she said.
Jessie Huang in the Yale Department of Computer Science and Patrick Wong in the Department of Immunobiology are co-lead authors of the paper. Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology, is co-corresponding author.
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Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

Melanoma patients receiving therapy that helps their immune system kill cancer cells respond to treatment differently depending on the types of microbes in their gut, and new research suggests the microorganisms hindering therapy have more influence than the beneficial ones.
Findings by a collaboration that included researchers at Oregon State University, the National Cancer Institute, the Frederick National Laboratory for Cancer Research and the University of Pittsburgh were published today in Nature Medicine.
The research is a key step forward in the fight against multiple types of cancer including melanoma, the most deadly form of skin cancer, said Andrey Morgun of the OSU College of Pharmacy.
“Our findings shed new light on the highly complicated interaction between the gut microbiome and cancer immunotherapy response and set a course for future studies,” he said.
Nationwide, melanoma is the fifth-most common cancer. Roughly 100,000 new melanoma cases will be diagnosed in the United States in the coming year, and more than 7,000 of those patients are expected to die, according to the American Cancer Society.
One of the most aggressive cancers, melanoma kills by metastasizing, or spreading, to other organs such as the liver, lungs and brain.

Three recent developments — incremental and undramatic but encouraging — are likely to improve the lives and health of seniors.The Covid pandemic has presented older Americans with plenty of grim news, from staffing shortages in long-term care and hospices to the punishing effects of loneliness and isolation. But there have been encouraging developments too — the kind of incremental progress that can take years to achieve, as lawsuits wend their way through courts, bills die in state legislatures and rise again, and the pandemic complicates everything.The results are not always dramatic, but they can improve lives and health for older people, especially those with low income. Here are three.A New Right to Appeal Medicare DecisionsFirst, a federal appellate court recently ruled that if Medicare declines to pay for your rehabilitation in a nursing home after you’ve left the hospital, because you were “on observation,” you can appeal the decision.This issue has boggled patients and families for years. You were in a hospital bed, doctors and nurses provided care, you were examined and perhaps received medication, but you were not actually admitted. Or you were, and then the hospital changed your status to “on observation.” Technically you were an outpatient, not an inpatientBut Medicare requires three consecutive days as an inpatient for you to be eligible for nursing home coverage. So you are left either having to pay the tab yourself (the national average nursing home cost is $260 a day) or forgoing care. In fact, if you are among the 9 percent of Medicare beneficiaries who don’t have Part B, which covers outpatient care, you must pay the hospital bill, too.Hundreds of thousands of patients discharged from hospitals have probably faced this conundrum. “You can appeal just about every issue regarding your Medicare coverage, but not that one,” said Alice Bers, litigation director at the Center for Medicare Advocacy.To change this, the center — along with Justice in Aging and a private law firm — sued the federal Department of Health and Human Services in 2011.Last month, the U.S. Court of Appeals for the Second Circuit affirmed that Medicare beneficiaries have a constitutional right to appeal if hospitals reclassify them as observation patients. If patients win their appeals, traditional Medicare will pay for up to 100 days of nursing home care, and those who were previously forced to pay out-of-pocket could receive refunds. (Medicare Advantage plans don’t generally require the three-day stay.)The Center for Medicare Advocacy answers frequent questions here.One catch: The government could still ask the Supreme Court to take the case, or seek a rehearing by the Second Circuit court. And the Medicare appeals process is no picnic. “People have the best chance of winning if they persist and work their way up through the levels,” Ms. Bers said.Repealing the three-day requirement would take Congressional action. But at least with the right to appeal, you have a fighting chance.California Eases Medicaid QualificationsIn a second promising development, California is eliminating asset limits for older people who are trying to qualify for Medicaid, and other states are considering similar moves.Medicaid, the state and federal program that provides health care for the poor and for people with disabilities, and also pays for long-term care in nursing homes and at home, sets strict ceilings on recipients’ wealth. In most states, if you are older than 65, you can amass no more than $2,000 in assets, or $3,000 for a couple (usually with a home and a car exempted).“It makes people live in very deep poverty,” unable to save for emergencies or even modest expenditures, said Amber Christ, director of health care policy and advocacy for Justice in Aging. “If you go over the limit by a dollar, you lose eligibility.”California will abolish this ceiling in two steps. In July, the asset limit rises to $130,000 for an individual and another $65,000 for each family member. In July 2024, the state will discard asset limits altogether. If you are older or disabled, you will qualify for Medi-Cal (as California calls its Medicaid program) if your income does not exceed 138 percent of the federal poverty level. The state estimates that about 17,000 residents will become newly eligible.Gov. Kathy Hochul of New York has incorporated a similar measure in her proposed state budget, eliminating asset limits as of Jan. 1, 2023; the state legislature will tackle the budget in March. Arizona eliminated asset limits in 2001, although not for long-term care, and other states are looking into the approach, Ms. Christ said.One catch: This year, 138 percent of the federal poverty level amounts to an annual income of $17,774. Medi-Cal recipients must still be poor, but less poor than before, and will be better able to hold onto their health coverage.Social Security Offices to ReopenOffices closed since the beginning of the pandemic will reopen.Fred Prouser/ReutersIn a third piece of a good news, the Social Security Administration has finally announced that it will soon reopen its 1,200 local offices.Except for limited “dire need” appointments made at the discretion of managers, offices have remained closed since the pandemic hit in March of 2020. Now, said Mark Hinkle, a spokesman for the agency, “we anticipate that local field offices will restore increased in-person service to the public, without an appointment, in early April.”This matters. “There are things that have to be done in person for Social Security,” said Kate Lang, senior staff attorney at Justice in Aging. You can apply online for retirement benefits but not for survivors’ benefits or for Supplemental Security Income, or S.S.I., which helps support seniors with very low income.These in-person requirements have meant that hundreds of thousands of applicants who would normally walk into local Social Security offices, carrying the required original documents, have been out of luck for two years.Moreover, “people already on benefits have gotten notices saying their benefits are being reduced or discontinued, and they’re unable to get in touch with anyone at Social Security to find out what’s going on,” Ms. Lang said. “There’s no way to fix these problems.”Trying to reach Social Security by phone can be an exercise in frustration. A report from the agency’s inspector general found that monthly calls to field offices rose from 4.6 million before the pandemic to 7.5 million in April through September 2020, and to 12 million in March of 2021. If you called field offices or the national 1-800 number, you often encountered busy signals or long waits; many callers abandoned the effort.Even after the Social Security Administration agreed to reopen offices, protracted negotiations with its uneasy employees followed. But the agency and its unions have reached agreements, although they are still working out the logistics of reopening.One catch: Visitors to a field office will likely face occupancy limits, and the agency must cope with huge backlogs. In an email, Mr. Hinkle said that the agency encourages the public to use its online or phone services when possible and to schedule in-person appointments in advance.Ms. Lang noted: “It’s not like everything will be hunky dory on April 1.” In fact, Justice in Aging has brought a class-action suit against the Social Security Administration on behalf of S.S.I. recipients who were unable to provide information or challenge decisions while offices were shuttered.But, Mr. Hinkle said, offices will reopen this spring “dependent on the course of the pandemic” — indisputably a good thing.